Copper(I)-Catalyzed Formal Carboboration of ... - ACS Publications

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Copper(I)-Catalyzed Formal Carboboration of Alkynes: Synthesis of Tri- and Tetrasubstituted Vinylboronates Ricardo Alfaro,† Alejandro Parra,† José Alemán, José Luis García Ruano, and Mariola Tortosa* Departamento de Química Orgánica (módulo 01), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain S Supporting Information *

is hampered by the use of highly sensitive boryllithium intermediates and stoichiometric amounts of copper. Additionally, the diisopropylbenzene (Dip) diamino group had to be transformed into a pinacolate group for further functionalization.9 Hoveyda,10 Yun,11 Ito,12 and more recently Carretero and Gómez-Arrayás13 have reported the related Cu-catalyzed hydroboration of alkynes (Scheme 1, eq 2).14,15 Although vinylcopper species are proposed as intermediates, their further reaction with an alkyl halide has never been reported. Herein, we describe the first Cu-catalyzed formal syn carboboration of simple alkynes (Scheme 1, eq 3). The reaction proceeds without directing groups to create both a C−B and a C−C bond, in a single catalytic cycle, using commercially available bis(pinacolato)diboron. To start our carboboration studies we first focused on cisbranched methyl vinylboronates. These boronic esters are direct precursors of cis-branched methylalkenes, widely found in natural products16 and also prominent in drugs and biologically active compounds (Figure 1).17 However, stereo-

ABSTRACT: The first copper-catalyzed formal carboboration of alkynes, in which a C−B bond and a C−C bond are created in a single catalytic cycle, is presented. The reaction proceeds with high regioselectivity and synstereoselectivity to form tri- and tetrasubstituted vinylboronic esters from commercially available bis(pinacolato)diboron. A subsequent cross-coupling reaction gives access to highly substituted alkenes.

V

inylboronates play an important role in organic synthesis.1 Their utility as partners in the Suzuki−Miyaura coupling reaction2 and their ability to undergo Rh-catalyzed3 and metalfree 4 conjugate additions make them highly versatile intermediates in the synthesis of complex molecules. Several approaches have been developed for the synthesis of disubstituted vinylboronic esters.1 However, methods to synthesize tri-5 and tetrasubstituted6 vinylboronates are significantly more limited. Among them, metal-catalyzed carboboration reactions are the most direct way to access these highly substituted vinylboronic esters. An excellent work by Suginome described the palladium- and nickel-catalyzed carboboration reactions of alkynes.7 However, despite the importance of these transformations, they usually require an alkyne functionalized with a hydroxyl group to promote an intramolecular boron addition and/or the use of boron sources which are difficult to handle.8 Consequently, it would be desirable to find carboboration conditions that required less expensive metals, nonfunctionalized alkynes and commercially available boron sources. Recently, the copper-mediated carboboration of propiolates has been developed (Scheme 1, eq 1). Unfortunately, the synthetic application of this reaction

Figure 1. Biologically active methyl-branched alkenes.

selective methods to synthesize cis-branched methyl alkenylboronates are still limited,18 especially those in which a C−B and a C−Me bond are created in a single catalytic cycle.19 Therefore, a Cu-catalyzed methylboration of alkynes would be an interesting approach to this class of boronic esters. Based on the proposed catalytic cycle for the Cu-catalyzed hydroboration (blue in Scheme 2), we reasoned that a methylboration (red in Scheme 2) would require the presence of an electrophile (MeI instead of MeOH) and the use of at least 1 equiv of NaOt-Bu (instead of the 0.2 equiv usually required for hydroboration). The CuI formed by reaction of the vinylcopper intermediate with MeI would be transformed into the catalytically active CuOt-Bu. Under these conditions, the

Scheme 1. Cu-Catalyzed Carboboration of Alkynes

Received: April 24, 2012

© XXXX American Chemical Society

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dx.doi.org/10.1021/ja307670k | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Scheme 2. Comparison of the Catalytic Cycles of the CuCatalyzed Hydroboration and Carboboration (Present Work)

Table 2. Cu(I)-Catalyzed Methylboration of Aryl-Substituted Alkynes

carboboration of alkynes would be possible if the vinyl cuprate intermediate were reactive enough to interact with MeI and if the catalyst or excess of NaOt-Bu did not interfere with the electrophile.20 We began by examining the methylboration of phenylacetylene 2a with bis(pinacolato)diboron 1 and methyl iodide in the presence of catalytic amounts of a ligand (10 mol%), CuCl (10 mol%), and NaOt-Bu (Table 1). The use of xantphos

NaOt-Bu (equiv)

ligandb

MeI (equiv)

yieldc (%)

3:4d

1 2 3 4 5 6e

1.1 0.6 1.1 1.1 1.1 1.1

xantphos xantphos PPh3 dppe xantphos xantphos

2.0 2.0 2.0 2.0 4.0 4.0

68 26 60 30 74 72

92:8 92:8 90:10 80:20 >98:2 >98:2

R1

R2

product

yieldd (%)

1a 2a 3a 4a 5b 6b 7a 8a 9a 10a 11a 12b 13b 14c 15c 16c

C6H5, 2a p-MeC6H4, 2b p-t-BuC6H, 4 2c m-MeC6H4, 2d p-MeOC6H4, 2e o-MeOC6H4, 2f p-FC6H4, 2g p-BrC6H4, 2h m-FC6H4, 2i 3,5-(CF3)2-C6H3, 2j p-(CH3CO2CH2)C6H4, 2k 2,4,5-(CH3)3-C6H2, 2l 2-thienyl, 2m C6H 5, 2n C6H5, 2o 3,5-(CF3)2-C6H3, 2p

H H H H H H H H H H H H H Me C6H5 Me

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p

74 68 83 75 76 80 72 72 66 _ 70 81 83 50 50 70

a

Conditions: xantphos, 0.1 M in THF, 16 h, rt. bConditions: xantphos, 0.6 M in THF, 24 h, rt. cConditions: P(p-tolyl)3, 0.6 M toluene, 24 h, 60 °C. dYield of isolated 3.

We observed that strong electron-donating groups at the para and ortho positions (2e and 2f) diminished the rate of methylboration, needing higher concentrations and longer reaction times (entries 5 and 6). Halogen-containing alkynes 2g−i selectively gave the methylboration products in good yields (entries 7−9). 2 1 Unfortunately, the 3,5-bis(trifluoromethyl)phenyl derivative 2j did not react, probably due to deprotonation of the alkyne in the presence of the alkoxide (entry 10). Base-sensitive functional groups such as acetates were compatible with the methylboration conditions (entry 11). Alkyne 2l, with a trisubstituted aryl ring, and thienyl substituted 2m also underwent the methylboration reaction in excellent yields (entries 12 and 13). Poor yields were obtained from nonterminal alkynes 2n,o using xantphos as ligand. However, after searching for different conditions (see Supporting Information for details), we were able to improve the results by heating the reaction to 65 °C with triptolylphosphine (entries 14−16). The best result was obtained with alkyne 2p (entry 16) bearing two electron withdrawing groups on the aromatic ring. One stereoisomer was exclusively formed in all cases, resulting from the syn addition of the methyl and boron groups. We then explored the methylboration of alkyl-substituted alkynes. While simple alkyl terminal alkynes did not react under the conditions described above, those bearing an ether moiety at the propargylic position gave good results (Scheme 3). Propargylic ether 2q afforded vinylboronate 3q as a single regio- and stereoisomer. Importantly, the methylboration conditions did not promote the formation of di- or triborylated compounds by β-oxygen elimination from vinylcopper species.14 Acetals were also compatible with the methylboration conditions and alkyne 2r gave protected aldehyde 3r, which is a very versatile synthetic intermediate. Additionally, we were pleased to find that tertiary ether 2s also gave the methylboration product in good yield as a single compound.

Table 1. Cu(I)-Catalyzed Methylboration of Alkyne 2a

entrya

entry

a

Conditions: 0.1 M in THF, 16 h, rt. bAbbreviations: xantphos = 4,5bis(diphenylphosphino)-9,9-dimethylxanthene; dppe = 1,2-bis(diphenylphosphino)ethane. cYield of isolated 3a. dDetermined by 1 H NMR analysis. e5 mol% CuCl and 5 mol% xantphos were used.

and 1.1 equiv of NaOt-Bu at room temperature gave the desired product 3a, along with a small amount of the hydroboration product 4a (entry 1). The yield decreased using 0.6 equiv of the alkoxide, verifying our initial hypothesis (entry 2). Triphenylphosphine (entry 3) or a diphosphine with a smaller bite angle (entry 4) did not improve the result. Finally, we found that by adding 4 equiv of the electrophile we could suppress the formation of 4a and 3a was obtained in good yield as a single regio- and stereoisomer. Additionally, the catalyst loading could be reduced to 5% without affecting the yield (entry 6). Next, we applied the optimized conditions to different arylsubstituted terminal (entries 1−13) and nonterminal (entries 14−16) alkynes (Table 2). Alkynes 2b−d, with alkyl groups at the para and meta positions, afforded (E) trisubstituted vinylboronates 3b−d as single regioisomers (entries 1−4). B



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place in good yield but very poor regioselectivity. The result observed for 9b is in contrast with that found for the Cucatalyzed hydroboration of similar alkynes.12 Under hydroboration conditions, only the regioisomer related to 10 was obtained with PPh3, while complete hydroboration of the double bond of the enyne was observed with xantphos. Interestingly, 2-substituted and 1,2-disubstituted enynes 9c (R1, R2, R4 = H, R3 = Me) and 9d (R1, R4 = H, R2, R3 = −(CH2)4−) afforded the methylboration products 10c−d as single compounds. Additionally, nonterminal enyne 9e (R1, R2 = H, R3 = Me, R4 = Et) gave tetrasubstituted vinylboronate 10e along with a small amount of the regioisomer 11e.25 Together, these data and those in Scheme 4 would suggest that the carboboration reaction mechanism differs significantly from the generally accepted Cu-catalyzed hydroboration mechanism. The vinylboronates obtained in this study are useful synthetic intermediates for the synthesis of trisubstituted alkenes (Scheme 6). The coupling of thienyl derivative 3m with ethyl

Scheme 3. Cu(I)-Catalyzed Methylboration of PropargylicFunctionalized Alkynes

The introduction of other electrophiles was then addressed (Scheme 4). Surprisingly, the reaction of 2a with allyl bromide Scheme 4. Cu(I)-Catalyzed Carboboration of Alkynes

Scheme 6. Synthetic Applications of Vinylboronic Esters

gave only allylation at the terminal position of the alkyne.22 Hoping to avoid this problem, we then explored the reaction of a nonterminal alkyne, 2o, with allyl iodide and benzyl bromide. Gratifyingly, we obtained the desired compounds 6o and 7o in moderate to good yields. Reaction of benzyl bromide with the nonsymmetrical alkyne 2n also gave the benzylated carboboration product but as a mixture of regioisomers 7n and 8n.23 This result is in contrast with those obtained with 2n under hydroboration11 and methylboration (Table 2, entry 14) conditions in which only one regioisomer was obtained and suggests that the electrophile is playing a role in the control of the regiochemistry of the reaction. Importantly, we did not observe borylation of the benzyl bromide in any case.20,24 These results provide the first evidence that intermediates in the Cu-catalyzed hydroboration reactions can be trapped by different electrophiles. Finally, we explored the methylboration of the more challenging 1,3-enynes (Scheme 5). With enynes 9a (R1, R3, R4 = H, R2 = C6H13) and 9b (R1, R3 = H, R2 = C6H13, R4 = Bu), and using either PPh3 or xantphos, the methylboration took

4-iodobenzoate, with concomitant hydrolysis of the methyl ester, afforded namirotene derivative 12 in good yield. Additionally, alkenes 13a and 13g were prepared in good overall yield through a one-pot methylboration-Suzuki coupling sequence from commercially available alkynes, allowing an easy entry to trisubstituted alkenes. In summary, we have developed the first copper-catalyzed formal carboboration of alkynes. Through this process, highly functionalized vinyl pinacol boronic esters can be obtained from readily available starting materials. Additionally, the onepot methylboration-Suzuki coupling sequence allows rapid access to highly functionalized alkenes, which are fundamental building blocks in organic synthesis. Some of the results disclosed in this paper suggest significant differences between the hydro- and the carboboration reactions. Mechanistic studies to understand these discrepancies are underway.

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Scheme 5. Cu(I)-Catalyzed Methylboration of 1,3-Enynes

ASSOCIATED CONTENT

S Supporting Information *

Experimental procedures and spectral data for new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

[email protected] Author Contributions †

R.A. and A.P. contributed equally to this work.

Notes

The authors declare no competing financial interest. C



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(17) The following are selected examples of branched methylcontaining natural products with important biological activity. (a) Epothilone A: Höfle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.; Reichenbach, H. Angew. Chem., Int. Ed. 1996, 35, 1567. (b) Rapamycin: Vézina, C.; Kudelski, A.; Sehgal, S. N. J. Antibiot. 1975, 28, 721. (c) Calyculin A: Suganuma, M.; Fujiki, H.; Furaya-Suguri, H.; Yoshizawa, S.; Yasumoto, S.; Kato, Y.; Fusetani, N.; Sugimura, T. Cancer Res. 1990, 50, 3521. (18) Methylalumination of alkynes followed by transmetalation with MeOBR2: (a) Negishi, E.; Boardman, L. D. Tetrahedron Lett. 1982, 23, 3327. Platinum-catalyzed dehydrogenative borylation: (b) Ohmura, T.; Takasaki, Y.; Furukawa, H.; Suginome, M. Angew. Chem., Int. Ed. 2009, 48, 2372. (19) To our knowledge, the only example reported to date requires the use of a palladium catalyst, a methylzirconium reagent, and an internal alcohol to promote the boron insertion. See ref 7e. (20) For a copper-catalyzed borylation of primary alkyl halides under similar conditions, see: (a) Yang, C.-T.; Zhang, Z.-Q.; Tajuddin, H.; Wu, C.-C.; Liang, J.; Liu, J.-H.; Fu, Y.; Czyzewska, M.; Steel, P. G.; Marder, T. B.; Liu, L. Angew. Chem., Int. Ed. 2012, 51, 528. (b) Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890. (21) For a copper-catalyzed borylation of aryl bromides under similar conditions, see: Kleeberg, C.; Dang, L.; Lin, Z.; Marder, T. Angew. Chem., Int. Ed. 2009, 48, 5350. (22) When we used 1 equiv of CuCl we obtained the allylated product in 50% yield. In contrast, we did not observe methylation of 2a when we used MeI as electrophile (Table 2). (23) The experiments and computational investigation of the coppercatalyzed hydroboration carried out by Hoveyda (see ref 13) do not support a reversible Cu−B addition to the alkyne. Their study indicates that catalyst−substrate association is product-determining. Although we do not have enough evidence, our results suggest that the electrophile and/or the excess of NaO-tBu are playing an important role in that catalyst−substrate association. (24) Despite this observation, we cannot rule out a mechanistic pathway involving a copper-catalyzed borylation of the alkyl halide followed by carboboration. Additional experimental studies are underway. (25) We could not determine the yield for 6e due to stability issues found during its purification. See Supporting Information.

ACKNOWLEDGMENTS Financial support from Spanish Government (CTQ-200912168) and CAM (“programa AVANCAT CS2009/PPQ1634”) is gratefully acknowledged. J.A. and M.T. thank the MICINN for “Ramon y Cajal” contracts, and R.A. thanks the “Consejo Nacional de Ciencia y Tecnologiá de México” for a postdoctoral fellowship.

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REFERENCES

(1) Hall, D. In Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine; Wiley-VCH: Weinheim, 2005. (2) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (3) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829. (4) Wu, T. R.; Chong, M. J. J. Am. Chem. Soc. 2007, 129, 4908. (5) Trisubstituted vinylboronates were synthesized through a threestep procedure involving the initial preparation of a vinyl iodide from an alkyne, followed by lithium−halogen exchange and trapping of the vinyllithium with triisopropoxyborane: (a) Uenishi, J.; Matsui, K.; Wada, A. Tetrahedron Lett. 2003, 44, 3093. For a route that involves haloboration of alkynes with boron tribromide followed by Negishi coupling, see: (b) Wang, C.; Tobrman, T.; Xu, Z.; Negishi, E. Org. Lett. 2009, 11, 4092. (c) Satoh, Y.; Serizawa, H.; Miyaura, N.; Hara, S.; Suzuki, A. Tetrahedron Lett. 1988, 29, 1811. Rhodium-catalyzed deshydrogenative borylations of vinylarenes and 1,1-disubstituted alkenes have been applied to the synthesis of 1,1-disubstituted vinylboronates: (d) Coapes, R. B.; Souza, F. E. S.; Thomas, R. Ll.; Hall, J. J.; Marder, T. B. Chem. Commun. 2003, 614. (6) For the synthesis of tetrasubstituted vinylboronates, see: (a) Hata, T.; Kitagawa, H.; Masai, H.; Kurahashi, T.; Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2001, 40, 790. (b) Shimizu, M.; Nakamaki, C.; Shimono, K.; Schelper, M.; Kurahashi, T.; Hiyama, T. J. Am. Chem. Soc. 2005, 127, 12506. (c) Itami, K.; Kamei, T.; Yoshida, J. J. Am. Chem. Soc. 2003, 125, 14670. (d) Nishihara, Y.; Miyasaka, M.; Okamoto, M.; Takahashi, H.; Inoue, E.; Tanemura, K.; Takagi, K. J. Am. Chem. Soc. 2007, 129, 12634. (e) Endo, K.; Hirokami, M.; Shibata, T. J. Org. Chem. 2010, 75, 3469. (f) Hupe, E.; Marek, I.; Knochel, P. Org. Lett. 2002, 4, 2861. (7) (a) Suginome, M.; Yamamoto, A.; Murakami, M. J. Am. Chem. Soc. 2003, 125, 6358. (b) Yamamoto, A.; Suginome, M. J. Am. Chem. Soc. 2005, 127, 15706. (c) Suginome, M.; Yamamoto, A.; Murakami, M. Angew. Chem., Int. Ed. 2005, 44, 2380. (d) Suginome, M.; Shirakura, M.; Yamamoto, A. J. Am. Chem. Soc. 2006, 128, 14438. (e) Daini, M.; Yamamoto, A.; Suginome, M. J. Am. Chem. Soc. 2008, 130, 2918. (f) Daini, M.; Suginome, M. Chem Comm 2008, 5224. (8) References 7a and 7c require the use of cyanoboranes, which can generate hydrogen cyanide by hydrolysis. References 7b, 7e, and 7f require the synthesis of air-sensitive chloroaminoboranes. (9) (a) Okuno, Y.; Yamashita, M.; Nozaki, K. Angew. Chem., Int. Ed. 2011, 50, 920. (b) Okuno, Y.; Yamashita, M.; Nozaki, K. Eur. J. Org. Chem. 2011, 3951. (10) Jang, H.; Zhugralin, A. R.; Lee, Y.; Hoveyda, A. M. J. Am. Chem. Soc. 2011, 133, 7859. (11) (a) Kim, H. R.; Jung, I. G.; Yoo, K.; Jang, K.; Lee, E. S.; Yun, J.; Son, S. U. Chem. Commun. 2010, 46, 758. (b) Kim, H. R.; Yun, J. Chem. Commun. 2011, 47, 2943. (12) Sasaki, Y.; Horita, Y.; Zhong, C.; Sawamura, M.; Ito, H. Angew. Chem., Int. Ed. 2011, 50, 2778. (13) Moure, A. L.; Gómez-Arrayás, R.; Cárdenas, D. J.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc. 2012, 134, 7219. (14) For a copper-catalyzed di- and triborylation of alkynes, see: Yoshida, H.; Kawashima, S.; Takemoto, Y.; Okada, K.; Ohshita, J.; Takaki, K. Angew. Chem., Int. Ed. 2012, 51, 235. (15) For a hydroboration that requires stoichiometric amounts of a Cu complex, see: Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2001, 625, 47. (16) Negishi, E.; Wang, G.; Rao, H.; Xu, Z. J. Org. Chem. 2010, 75, 3151. D


Copper(I)-Catalyzed Formal Carboboration of ... - ACS Publications

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